Discovery and Synthesis of a Naturally Derived Protein Kinase Inhibitor that Selectively Inhibits Distinct Classes of Serine/Threonine Kinases.

ABSTRACT: The DNAJB1-PRKACA oncogenic gene fusion results in an active kinase enzyme, J-PKAcα, that has been identified as an attractive antitumor target for fibrolamellar hepatocellular carcinoma (FLHCC). A high-throughput assay was used to identify inhibitors of J-PKAcα catalytic activity by screening the NCI Program for Natural Product Discovery (NPNPD) prefractionated natural product library. Purification of the active agent from a single fraction of an Aplidium sp. marine tunicate led to the discovery of two unprecedented alkaloids, aplithianines A (1) and B (2). Aplithianine A (1) showed potent inhibition against J-PKAcα with an IC₅₀ of ∼1 μM in the primary screening assay. In kinome screening, 1 inhibited wild-type PKA with an IC₅₀

SUBMITTER: Du L 

PROVIDER: S-EPMC10616853 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature